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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53.
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PMID:Bcl-XL protects cancer cells from p53-mediated apoptosis. 747 61

The tumor suppressor gene p53 regulates G1 checkpoint prior to the initiation of DNA synthesis, which can either induce G1 arrest or signal apoptosis. The involvement of p53 in apoptosis may also be related to its ability to down-regulate transcription of the bcl-2 gene. The bcl-2 gene product prevents most types of apoptotic cell death, suggesting that bcl-2 interferes with an essential signaling molecule involved in the apoptotic cell death pathway. Although the bcl-2 protein is shown to be overexpressed in many types of human tumor including breast cancer, its biochemical or pathological consequences are poorly understood. To determine the effects of bcl-2 overexpression on apoptosis and transformation of breast epithelial cells and to investigate whether bcl-2 interferes with the p53 pathway, we introduced the bcl-2 expression vector into MCF10A cells, which were derived from diploid human breast epithelial cells containing the wild-type p53 gene. Overexpression of bcl-2 prevented free radical-induced apoptosis and induced a partially transformed phenotype in MCF10A cells. Although overexpression of bcl-2 did not affect the expression of the p53 gene, p53-dependent gene transcription such as p21WAF1/CIP1 was suppressed. These results suggest that bcl-2 may inhibit p53 functional activity and is involved in the regulation of an early commitment step either to proliferate or suicide.
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PMID:bcl-2 suppresses expression of p21WAF1/CIP1 in breast epithelial cells. 755 20

Expression of the bcl-2 proto-oncogene was studied immunohistochemically in 251 invasive ductal breast carcinomas (median follow-up time 91 months, range 24-186 months) and the results were correlated with clinicopathological data and prognostic variables. Sixty-three (25%) tumours were scored bcl-2 negative and 188 (75%) tumours were bcl-2 positive. No relationship could be observed between bcl-2 status and tumour grade, pTNM staging or menopausal status. A strong positive relationship was demonstrated between bcl-2 immunoreactivity and oestrogen receptor status (P < 0.001) and progesterone receptor status (P < 0.001). No prognostic value was demonstrated for bcl-2 expression on disease-free survival and overall survival in axillary node-negative breast cancer patients. However, in axillary node-positive breast cancer patients multivariate analysis demonstrated absence of bcl-2 expression to be independently related to shortened disease-free survival (P = 0.003) and shortened overall survival (P < 0.001). Our results suggest a potential important role for bcl-2 expression as a modulator of response to adjuvant therapy in breast cancer.
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PMID:Prognostic value of bcl-2 expression in invasive breast cancer. 764 Feb 18

The nuclear transcription factor Fos is inducible by both steroid hormones and peptide growth factors. It thus forms a potential point of interaction between steroid hormone- and growth factor-directed pathways and may be critical in the subversion of steroid hormone control in breast cancer. In this light, the present study has used immunocytochemistry to demonstrate in clinical primary breast cancer that Fos expression is indeed significantly associated with a failure to respond to endocrine therapy, with preliminary analysis revealing a survival advantage for those patients whose tumours lacked Fos. Sustained elevated levels of Fos expression were significantly associated with further factors, notably peptide growth factors and their receptors (e.g., EGFR, TGF alpha), as well as with the proliferation marker Ki-67, which have been linked previously to endocrine insensitivity in breast cancer. In contrast, there appeared to be a trend for Fos to be absent in those tumours expressing markers of endocrine responsiveness (e.g., oestrogen receptor [ER], and also ER-mediated markers i.e., PR, pS2 or bcl-2). Interestingly, many of these trends were maintained in ER+ patients, suggesting that Fos may be of importance in directing loss of endocrine sensitivity in ER+ disease.
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PMID:Immunocytochemical localization of Fos protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy. 765 91

The effects of the novel vitamin D analogue, EB1089 alone, or in combination with the retinoid, 9-cis retinoic acid (9-cis RA) on indices of apoptosis in MCF-7 breast cancer cells have been examined. EB1089 was capable of reducing bcl-2 protein, a suppressor of apoptosis, and increasing p53 protein levels in MCF-7 cell cultures following 96h treatment. In the presence of 9-cis RA, EB1089 acted to further enhance the down-regulation and up-regulation of bcl-2 and p53 respectively. Furthermore, EB1089 induces DNA fragmentation in MCF-7 cells, a key feature of apoptosis, alone and in combination with 9-cis RA in situ. The observation that EB1089 and 9-cis RA act in a cooperative manner to enhance induction of apoptosis in these cells may have therapeutic implications.
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PMID:Vitamin D derivatives in combination with 9-cis retinoic acid promote active cell death in breast cancer cells. 766 28

The bcl-2 gene encodes a protein which inhibits programmed cell death (apoptosis). This protein was detected by immunohistochemical techniques in 48% of invasive ductal carcinomas of the breast. It was present in well-differentiated carcinomas with hormonal receptors, and proteins synthesized under the control of oestrogens: pS2, cathepsin D and ERD5. In contrast, bcl-2+ carcinomas are less frequently positive for p53 and have a Ki67 score under the mean. bcl-2 protects cells against apoptosis. Accumulation of p53 protein, which is indicative of p53 mutation, would have the same effect; however, these two proteins seem inversely related, an inverse correlation observed by others in breast cancer cell lines and in lymphomas. Tumours positive for bcl-2 escape apoptosis and have worse prognosis but this is not what is found; survival at 5 years, and particularly the absence of recurrence during the first 5 years after surgery, seem to be associated with bcl-2 positivity. The bcl-2 protein seems only to be an important prognostic factor in women over 54 years of age. Moreover, p53-bcl-2+ tumours have a better response to hormonal therapy than p53-bcl-2-tumours.
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PMID:bcl-2 protein in invasive ductal breast carcinomas. 775 87

We utilized a reverse transcription-PCR method to examine the effect of estrogen on the expression of mRNA for Bcl-2 and Bax, two modulatory proteins in the apoptotic pathway, in human breast cancer cell line MCF-7. We found that the bcl-2 mRNA levels in the cells exposed to 17 beta-estradiol were higher than those of control cells. Although the relative bax mRNA levels remained unchanged, the changes in bcl-2 mRNA level occurred in a time- and concentration-dependent fashion. In addition, pretreatment with 17 beta-estradiol protected MCF-7 cells from apoptosis. Our study provides evidence that responses of breast epithelial cells toward a steroid sex hormone involve regulation of the apoptotic pathway.
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PMID:Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. 778 Sep 52

We have studied the in vitro biological activities and mechanism of action of 1,25-dihydroxyvitamin D3 (1,25D3) and four potent 1,25D3 analogues [20-epi-22oxa-24a,26a,27a-tri-homo-1,25(OH)2D3 (KH 1060); 20-epi-1,25(OH)2D3; 1,25(OH)2-16ene-D3; and 1,25(OH)2-16ene-23yne-D3] on proliferation and differentiation of estrogen receptor-negative (MDA-MB-436, BT-20, SK-BR-3, and MDA-MB-231), estrogen receptor-weakly positive (BT474), and estrogen receptor-positive (MCF-7) breast cancer cell lines. Dose-response studies showed that KH 1060 was the most potent analogue, because it was able to induce differentiation in all seven breast cancer cell lines (measured by lipid staining) and to suppress more than 50% clonal proliferation (ED50) at 10(-10) M in all cell lines, except MDA-MB-436 and BT-20. To explore how these compounds mediated antiproliferative actions, their effects on the cell cycle, on expression of bcl-2 and p53, and on apoptosis were assessed. Five of six cell lines have a mutant p53 gene, whereas MCF-7 has wild-type p53. Immunohistochemical staining showed that the p53 protein was predominantly localized in the nucleus in each of the breast cancer cell lines except for MCF-7, which expressed the protein predominantly in the cytoplasm. After incubation with KH 1060 (3 days; 10(-7) M), expression of bcl-2 protein as determined by immunohistochemical localization was markedly decreased in BT-474, MCF-7, and MDA-MB-231; these same cells were profoundly inhibited in their clonal proliferation and arrested in the G0/G1 phase of the cell cycle when cultured with KH 1060. In contrast, BT-20 and MDA-MB-436 cells that were refractory to the antiproliferative effect of KH 1060 (ED50 < 10(-6) M) had no down-regulation of their bcl-2 expression and no cell cycle changes after exposure to KH 1060. MCF-7 showed morphological changes and DNA fragmentation, indicative of apoptosis after 48 h incubation with KH 1060 (10(-6) M), during which time p53 protein accumulated in the nucleus and decreased in the cytoplasm. In contrast, no apoptosis was detected in three other breast lines (MDA-MB-231, SK-BR-3, and BT-474) that had a mutated p53. In conclusion, the data indicate that KH 1060 is an extremely potent 1,25D3 analogue inducing differentiation of all six breast cancer lines and potently inhibiting clonal growth of four of them with concomitant decreased bcl-2 and cell cycle arrest at G0/G1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:20-epi-vitamin D3 analogues: a novel class of potent inhibitors of proliferation and inducers of differentiation of human breast cancer cell lines. 779 9

The expression of the bcl-2 proto-oncogene, which is associated with prolonged cell survival and prevention of programmed cell death, was investigated in human primary breast carcinomas prior to and following endocrine therapy with the anti-oestrogen, tamoxifen. Using the BCL-2-100 antibody, a 26-kD protein was detected by western immunoblot in the cytosols of oestrogen receptor (ER)+ve human breast cancers. In a cross-sectional study, the immunohistochemical expression of Bcl-2 was observed in 32% of invasive breast cancers, but in 65% of tumours treated with tamoxifen (P = 0.009). There was a significant association of Bcl-2 with ER status, with 64% of untreated and 88% of tamoxifen-treated Bcl-2-positive tumours being ER+ve. A significantly lower Ki-67 score was found in tamoxifen-treated tumours which were Bcl-2-positive compared with Bcl-2-negative (9.3 versus 24.6%, P = 0.01). In a separate series of sequential Trucut biopsies from 18 patients, the frequency of Bcl-2 expression was increased in ER+ve tumours from 3/12 to 8/11 following tamoxifen (P = 0.04). This was also associated with a significant reduction in mean Ki-67 score from 32 to 12% (P = 0.0004). The observations from this study clearly indicate that Bcl-2 in human breast cancer is associated with ER status, and that expression is enhanced in ER+ve tumours following tamoxifen, in association with reduced cell proliferation.
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PMID:Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen. 783 41

We have studied the expression of the apoptosis-regulating genes bcl-2, bcl-x, bax and APO-1/fas (CD95) in human breast cancer. The expression pattern of these genes in human breast-cancer tissues and breast-cancer-derived cell lines was compared to that seen in normal breast epithelium and breast epithelial cell lines. No difference with regard to bcl-2 and bcl-xL expression was observed between normal breast epithelium and tumor tissue or breast cancer and non-malignant epithelial cell lines. In contrast, bax-alpha, a splice variant of bax, which promotes apoptosis, is expressed in high amounts in normal cell lines and breast tissue, whereas only weak or no expression could be detected in cancer-cell lines and malignant tissue. In contrast to malignant cell lines, which express low levels of bax-alpha, non-malignant epithelial cell lines displaying high amounts of bax-alpha were highly sensitive to induction of programmed cell death by both serum starvation and APO-1/fas (CD95) triggering. We therefore propose that dysregulation of apoptosis contributes to the pathogenesis of breast cancer, at least in part, due to an imbalance between anti-apoptosis genes (such as bcl-2/bcl-x) and apoptosis-promoting genes (bax).
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PMID:Expression of the bcl-2 gene family in normal and malignant breast tissue: low bax-alpha expression in tumor cells correlates with resistance towards apoptosis. 789 58


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